扩大慢性乙型肝炎抗病毒治疗应重视ALT正常、年龄≤30岁的HBeAg阴性慢性HBV感染者

刘燕娜; 李明蔚; 王雷婕; 赵鸿; 党双锁; 陈香梅; 赵景民; 鲁凤民

doi:10.3969/j.issn.1001-5256.2022.07.006

扩大慢性乙型肝炎抗病毒治疗应重视ALT正常、年龄≤30岁的HBeAg阴性慢性HBV感染者

DOI: 10.3969/j.issn.1001-5256.2022.07.006

刘燕娜¹,
李明蔚²,
王雷婕¹,
赵鸿³,
党双锁⁴,
陈香梅¹,
赵景民^5, , ,,
鲁凤民^{1, 6, , ,}

1.
北京大学基础医学院病原生物学系暨感染病研究中心，北京 100191
2.
郑州大学公共卫生学院流行病学教研室，郑州 450001
3.
北京大学第一医院感染疾病科，北京 100034
4.
西安交通大学第二附属医院感染科，西安 710004
5.
中国人民解放军总医院第五医学中心病理科，北京 100039
6.
北京大学人民医院，北京大学肝病研究所，丙型肝炎和肝病免疫治疗北京市重点实验室，北京 100044

基金项目:

国家十三五“艾滋病和病毒性肝炎等重大传染病防治”科技重大专项基金 (2017ZX10302201)

伦理学声明：本研究方案于2022年1月27日经由解放军总医院第五医学中心伦理委员会审批，批号：KY-2022-1-4-1。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：鲁凤民、赵景民负责课题设计与指导；李明蔚、王雷婕负责收集数据与分析数据；赵鸿、党双锁、陈香梅对数据结果进行总结、解读；刘燕娜、鲁凤民、陈香梅负责拟定写作思路并起草文稿；所有作者均对文章关键内容做出修订并最后定稿。

详细信息

通信作者:
赵景民，jmzhao302@163.com

鲁凤民，lu.fengmin@hsc.pku.edu.cn

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出版历程
- 收稿日期: 2022-04-14
- 录用日期: 2022-05-24
- 出版日期: 2022-07-20

HBeAg-negative chronic HBV-infected individuals with normal alanine aminotransferase and an age of ≤30 years should be taken seriously when expanding anti-HBV treatment for chronic hepatitis B

1.
Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing 100191, China
2.
Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, China
3.
Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
4.
Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
5.
Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
6.
Peking University Hepatology Institute, Peking University People's Hospital, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing 100044, China

Research funding:

The National S & T Major Project for Infectious Diseases (2017ZX10302201)

More Information

Corresponding author: ZHAO Jingmin, jmzhao302@163.com(ORCID: 0000-0003-4345-2149); LU Fengmin, lu.fengmin@hsc.pku.edu.cn(ORCID: 0000-0002-1832-3209)

摘要

摘要: 目的拟对2022年2月发布的《扩大慢性乙型肝炎抗病毒治疗的专家意见》的推荐意见进行分析验证和完善。方法本研究为单中心回顾性研究，连续纳入2014年1月—2020年10月于中国人民解放军总医院第五医学中心接受肝穿刺活组织病理检查且ALT正常的成人慢性HBV感染者，并分析≤30岁和＞30岁亚组中不同HBeAg状态人群存在中、重度肝损伤人群比例。结果共纳入慢性HBV感染者290例，HBeAg阳性者121例(41.7%)，HBeAg阴性者169例(58.3%)。进一步按年龄分组，在HBeAg阳性中，≤30岁37例，＞30岁84例；在HBeAg阴性感染者中，≤30岁24例，＞30岁145例。4组比较，年龄(H=151.539)、性别(χ²=9.959)、ALT(H=29.041)、AST(H=11.127)、Alb(H=23.538)、HBV DNA(H=187.982)、HBsAg(H=132.520)组间比较差异均有统计学意义(P值均＜0.05)。年龄＞30岁和≤30岁组均有近50%的患者存在中度及以上肝损伤(50.22% vs 47.54%)。根据HBeAg状态和年龄进一步将患者分为HBeAg阳性≤30岁(n=37)和＞30岁(n=84)以及HBeAg阴性≤30岁(n=24)和＞30岁(n=145)共4组。在HBeAg阳性亚组中，＞30岁与≤30岁者存在中度及以上肝损伤的差异无统计学意义(42.9% vs 37.8%，P=0.605)；≤30岁的HBeAg阴性亚组与＞30岁的HBeAg阴性亚组存在中度及以上肝损伤的差异亦无统计学意义(62.5% vs 54.5%，P=0.464)。在无创指标无法决策的队列(LSM＜9.0 kPa者和LSM数据缺失但FIB-4＜3.25者，n=269)中，≤30岁的HBeAg阴性亚组与＞30岁的HBeAg阴性/阳性亚组存在中度及以上肝损伤的差异无统计学意义(59.1% vs 50.7%、59.1% vs 41.8%，P值分别为0.468、0.149)。结论在扩大抗HBV治疗时，也应关注HBeAg阴性且年龄≤30岁的慢性HBV感染者。条件允许时，依照本研究总结修订的抗病毒治疗启动线路图，或可进一步提高个体化抗病毒治疗的精准性。
- 乙型肝炎，慢性 /
- 肝炎e抗原, 乙型 /
- 年龄因素 /
- 丙氨酸转氨酶 /
- 抗病毒治疗
Abstract: Objective To validate and refine the recommendations in the recently published expert opinion on expanding anti-HBV treatment for chronic hepatitis B. Methods Adult individuals with chronic HBV infection and normal alanine aminotransferase (ALT) who underwent liver biopsy in The Fifth Medical Center of Chinese PLA General Hospital from January 2014 to October 2020 were enrolled in this single-center retrospective study, and the proportion of individuals with moderate or severe liver injury was analyzed in the population with different HBeAg status in the ≤30 years and > 30 years subgroups. Results A total of 290 individuals with chronic HBV infection were included, among whom 121 (41.7%) were HBeAg positive and 169 (58.3%) were HBeAg negative. The HBeAg-positive group and the HBeAg-negative group were further divided into subgroups according to age: in the HBeAg-positive group, 37 were aged ≤30 years and 84 were aged > 30 years; in the HBeAg-negative group, 24 were aged ≤30 years and 145 were aged > 30 years. There were significant differences between the four groups in age (H=151.539, P < 0.05), sex (χ²=9.959, P < 0.05), ALT (H=29.041, P < 0.05), aspartate aminotransferase (H=11.127, P < 0.05), albumin (H=23.538, P < 0.05), HBV DNA (H=187.982, P < 0.05), and HBsAg (H=132.520, P < 0.05). In both > 30 years and ≤30 years groups, nearly 50% of the patients had a moderate or higher grade of liver injury (50.22% vs 47.54%). According to HBeAg status and age, the patients were further divided into HBeAg-positive ≤30 years group with 37 patients, HBeAg-positive > 30 years group with 84 patients, HBeAg-negative ≤30 years group with 24 patients, and HBeAg-negative > 30 years group with 145 patients. In the HBeAg-positive group, there was no significant difference in the proportion of patients with a moderate or higher grade of liver injury between the patients aged > 30 years and those aged ≤30 years (42.9% vs 37.8%, P=0.605), and there was also no significant difference in such proportion between the HBeAg-negative ≤30 years group and the HBeAg-negative/positive > 30 years groups (62.5% vs 54.5%, P=0.464). In the cohort for which a decision could not be made based on noninvasive indices (269 patients with liver stiffness measurement < 9.0 kPa or without the data of liver stiffness measurement but with fibrosis-4 < 3.25), there was no significant difference in the proportion of patients with a moderate or higher grade of liver injury between the HBeAg-negative ≤30 years group and the HBeAg-negative/positive > 30 years groups (59.1% vs 50.7% and 59.1% vs 41.8%, P=0.468 and 0.149). Conclusion HBeAg-negative chronic HBV-infected individuals with an age of ≤30 years should be taken into consideration when expanding anti-HBV treatment for chronic hepatitis B. If conditions permit, the revised flow chart for the initiation of anti-HBV treatment based on this study can be applied to further improve the precision of individualized anti-HBV treatment.
- Hepatitis B, Chronic /
- Hepatitis B e Antigens /
- Age Factors /
- Alanine Transaminase /
- Antiviral Treatment

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图 1 依据《专家意见》总结修订的抗病毒治疗启动线路图

注：在参考文献[1]基础上补充修订。虚线表示笔者新增部分。本流程不包括“不确定期”慢性乙型肝炎患者启动抗病毒治疗的意见。

Figure 1. The revised flow chart from the expert opinion for initiation of anti-HBV treatment for chronic hepatitis B

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表 1 HBeAg阳性与阴性慢性HBV感染者一般资料比较

Table 1. Comparison of general data between HBeAg positive and HBeAg negative chronic HBV infection

指标	HBeAg阳性(n=121)		HBeAg阴性(n=169)		统计值	P值
指标	≤30岁(n=37)	＞30岁(n=84)	≤30岁(n=24)	＞30岁(n=145)	统计值	P值
年龄(岁)	26(23~29)¹⁾²⁾	39(34~47)²⁾³⁾⁴⁾	27(24~29)¹⁾²⁾	43(38~49)¹⁾³⁾⁴⁾	H=151.539	＜0.001
性别[例(%)]					χ²=9.959	0.019
男	22(59.5)	38(45.2)	18(75.0)²⁾	64(44.1)⁴⁾
女	15(40.5)	46(54.8)	6(25.0)²⁾	81(55.9)⁴⁾
ALT(U/L)	30(22~36)²⁾⁴⁾	25(19~32)²⁾	20(16~28)³⁾	20(15~27)¹⁾³⁾	H=29.041	＜0.001
AST(U/L)	25(21~31)²⁾	24(20~28)	21(18~25)	21(18~27)³⁾	H=11.127	0.011
ALP(U/L)	70(56~89)	72(59~92)	71(63~88)	72(59~89)	H=0.667	0.881
GGT(U/L)	14(11~19)	17(13~21)	17(14~25)	16(12~23)	H=4.941	0.176
Alb(U/L)	41(39~44)	39(37~42)²⁾⁴⁾	43(41~45)¹⁾	41(39~44)¹⁾	H=23.538	＜0.001
PA(mg/L)	199.6±44.2	194.0±42.3	215.6±40.7	205.2±44.7	F=1.988	0.116
PLT(×10⁹/L)	204(173~237)	200(158~230)	184(150~217)	188(158~225)	H=3.816	0.282
HBV DNA(log₁₀ IU/mL)	8.0(7.0~8.4)²⁾⁴⁾	8.0(7.4~8.3)²⁾⁴⁾	2.7(2.3~3.5)¹⁾³⁾	3.2(2.5~4.1)¹⁾³⁾	H=187.982	＜0.001
HBsAg(log₁₀ IU/mL)	4.5(3.9~4.7)²⁾⁴⁾	4.6(3.9~4.9)²⁾⁴⁾	3.3(3.1~3.6)¹⁾³⁾	3.2(2.6~3.6)¹⁾³	H=132.520	＜0.001
炎症分期[例(%)]						0.070
G0~G1	33(89.2)	64(76.2)	18(75.0)	127(87.6)
G2~G4	4(10.8)	20(23.8)	6(25.0)	18(12.4)
肝纤维化分期[例(%)]					χ²=6.459	0.091
S0~S1	24(64.9)	50(59.5)	10(41.7)	69(47.6)
S2~S4	13(35.1)	34(40.5)	14(58.3)	76(52.4)
存在明显肝损伤[例(%)]					χ²=6.556	0.087
否	23(62.2)	48(57.1)	9(37.5)	66(45.5)
是	14(37.8)	36(42.9)	15(62.5)	79(54.5)
注：与HBeAg阳性(＞30岁)者比较，1)P＜0.05；与HBeAg阴性(＞30岁)者比较，2)P＜0.05；与HBeAg阳性(≤30岁)者比较，3)P＜0.05；与HBeAg阴性(≤30岁)者比较，4)P＜0.05。

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表 2 无创指标无法决策抗病毒治疗者肝损伤情况比较

Table 2. Comparison of liver injury in patients with non-invasive indicators unable to determine antiviral therapy

是否存在明显肝损伤	HBeAg阳性		HBeAg阴性		χ²值	P值
是否存在明显肝损伤	≤30岁(n=34)	＞30岁(n=79)	≤30岁(n=22)	＞30岁(n=134)	χ²值	P值
否[例(%)]	23(67.6)	46(58.2)	9(40.9)	66(49.3)	5.819	0.121
是[例(%)]	11(32.4)	33(41.8)	13(59.1)	68(50.7)

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